A series of phthaloyl amino acid hydroxamic acids are useful as inhibitors of Angiotensin I converting enzyme.

Claim:

What is claimed is:

1. The compound N-(2-carboxybenzoyl)-D-histidine hydroxamic acid.

Description:

This invention is concerned with chemicalcompounds and particularly with phthaloyl amino acid hydroxamic acids of the formula: ##STR1## wherein A is methylene, ethylene or ##STR2## wherein R is methyl, imidazolylmethyl, isobutyl, benzyl or 4-aminobutyl and in which ##STR3## is in theD-configuration.

The members of this series are potent inhibitors of the enzyme responsible for the conversion of Angiotensin I to the powerful pressor agent Angiotensin II associated with hypertension. They are thus capable of interrupting the biologicalpathway leading to the formation of that active pressor substance. For example, they inhibit the pure converting enzyme isolated from rabbit lung tissue at levels of from 0.8 to 1.9 .times. 10.sup.-5 moles per liter.

The compounds of this invention are also capable of inhibiting the hypertensive effects induced by administration of Angiotensin I to animals. Infusion of these compounds at a rate of from 0.5 to 10 .mu.g./kg./min. intravenously inphysiologically acceptable menstrua such as isotonic saline to pithed rats counteracts the elevation in blood pressure induced by Angiotensin I by at least 50%.

The method which is currently preferred for the preparation of the compounds of this invention is shown by the following equation: ##STR4## wherein A has the significance given above. The base employed is an inorganic one such as potassiumhydroxide.

In order that this invention may be readily available to and understood by those skilled in the art, the following examples of the preparation of the compounds thereof are appended.

EXAMPLE I

3-(2-Carboxybenzamido)Propionohydroxamic Acid

A. Phthaloyl-.beta.-Alanine Hydroxamic Acid

Phthaloyl-.beta.-alanine (15.3 g, 0.07 m) was dissolved in dichloromethane (100 ml) and dimethylformamide (10 ml), cooled and a solution of dicyclohexylcarbodiimide (14.4 g, 0.07 m) in dichloromethane (50 ml) was added. In another flaskhydroxylamine hydrochloride (4.87 g, 0.077 m) was dissolved in dimethylformamide (70 ml), and triethylamine (10.75 ml, 0.077 m) was added. The mixture was cooled and filtered. The filtrate was added to the above cold stirred solution, refrigeratedovernight, filtered and the filtrate evaporated to dryness. The residue was crystallized from methanol/ethyl acetate. Yield: 13.0 g.

Recrystallization from ethyl acetate/petroleum ether gave the product, m.p. 146.degree..

Phthaloylglycine (43.1 g, 0.21 m) was dissolved in dichloromethane (300 ml) and dimethyl formamide (30 ml). The mixture was cooled and dicyclohexylcarbodiimide (44.2 g, 0.21 m) dissolved in dichloromethane (100 ml) was added. In a separateflask a mixture of hydroxylamine hydrochloride (16.05 g, 0.23 m), triethylamine (32.3 g, 0.23 m) and dimethylformamide (200 ml) was prepared, cooled, filtered and the filtrate added to the above cold, stirred solution. After standing in a refrigeratorovernight, the mixture was filtered and the filtrate was evaporated to an oil which crystallized from methanol/ethyl acetate to yield 17 g, m.p. 167.degree. (dec.), of 2-phthalamidoacetohydroxamic acid.